title: Pioglitazone alleviates the mitochondrial apoptotic pathway and mito-oxidative damage in the d-galactose-induced mouse model.
abstract: Chronic injection of d-galactose can cause gradual deterioration in learning and memory capacity, and activates oxidative stress, mitochondrial dysfunction and apoptotic cell death in the brain of mice. Thus, it serves as an animal model of ageing. Recent evidence has shown that mild cognitive impairment in humans might be alleviated by treatment with piogliatzone (peroxisome proliferator-activated receptor gamma (PPARγ) agonists). To continue exploring the effects of piogliatzone in this model, we focused on behavioural alteration, oxidative damage, mitochondrial dysfunction and apoptosis in d-galactose-induced mice. The ageing model was established by administration of d-galactose (100 mg/kg) for 6 weeks. Pioglitazone (10 and 30 mg/kg) and bisphenol A diglycidyl ether (15 mg/kg) were given daily to d-galactose-induced senescent mice. The cognitive behaviour of mice was monitored using the Morris water maze. The anti-oxidant status and apoptotic activity in the ageing mice was measured by determining mito-oxidative parameters and caspase-3 activity in brain tissue. Systemic administration of d-galactose significantly increased behavioural alterations, biochemical parameters, mitochondrial enzymes, and activations of caspase-3 and acetylcholinesterase enzyme activity as compared with the control group. Piogliatzone treatment significantly improved behavioural abnormalities, biochemical, cellular alterations, and attenuated the caspase-3 and acetylcholinesterase enzyme activity as compared with the control. Furthermore, pretreatment of BADGE (PPARγ antagonist) with pioglitazone reversed the protective effect of pioglitazone in d-galactose-induced mice. The present study highlights the protective effects of pioglitzone against d-galactose-induced memory dysfunction, mito-oxidative damage and apoptosis through activation of PPARγ receptors. These findings suggest that pioglitazone might be helpful for the prevention or alleviation of ageing.
authors.affiliation: Mental Health Research Institute, The University of Melbourne, Melbourne, VIC, Australia. atishprakash@gmail.com
authors.forename: Atish
authors.initials: A
authors.lastname: Prakash
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D005690:Galactose / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D047495:PPAR gamma; D045162:Thiazolidinediones; D000110:Acetylcholinesterase; D053148:Caspase 3; D005690:Galactose; D000077205:Pioglitazone
keywords: caspase-3; d-galactose; mitochondria; neuroprotection; senescence